The Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras) are part of a signaling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation. Mutated ras genes (Ha-ras, Ki4a-ras, Ki4b-ras and N-ras) are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias.
Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least three post-translational modifications are involved with Ras membrane localization, and all three modifications occur at the C-terminus of Ras. The Ras C-terminus contains a sequence motif termed a "CAAX" or "Cys-Aaa.sup.1 -Aaa.sup.2 -Xaa" box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature 310:583-586 (1984)). Depending on the specific sequence, this motif serves as a signal sequence for the enzymes farnesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C.sub.15 or C.sub.20 isoprenoid, respectively. (S. Clarke., Ann. Rev. Biochem. 61:355-386 (1992); W. R. Schafer and J. Rine, Ann. Rev. Genetics 30:209-237 (1992)).
The peptide derived inhibitors of farnesyl-protein transferase (FPTase) that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation. (Schaber et al., J. Biol. Chem., 265:14701-14704 (1990); Reiss et. al., Cell, 62:81-88 (1990); Reiss et al., PNAS, 88:732-736 (1991)). Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the farnesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S. Pat. No. 5,141,851, University of Texas; N. E. Kohl et al., Science, 260:1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)). In general, while deletion of the thiol from a CAAX derivative has been shown to reduce the inhibitory potency of the compound, the thiol group can adversely affect the pharmacokinetics, pharmacodynamics and toxicity of FPTase inhibitors. Consequently, functional replacements for the thiol group have been achieved.
Thiol replacements that incorporate a 1,5 disubstituted imidazole with a biaryl component have been observed to be FPTase inhibitors. The synthesis of 1,5 disubstituted imidazoles from primary amines, dihydroxyacetone and potassium thiocyanate via thioimidazoles has been reported in the classical literature (Marckwald, Chem Ber. 1892, 25, 2354; Duncia, J. M. et al, J. Med Chem. 1990, 33, 1312-1330; Jones, R. G., J. Am. Chem. Soc. 1949, 71, 383 and 644; Pyman, J. Chem. Soc. 1911, 99, 668). Literature protocols for the dethionation of 2-mercaptoimidazoles describe treatment with concentrated nitric acid, with or without a nitrite; such procedures give variable results and often result in the sudden violent release of nitrogen oxide gases.
Therefore, the need exists for a process for synthesizing 1,5 disubstituted imidazoles with biaryl components which has a predictably higher yield than known methods and which utilizes reaction conditions that are free from the drawbacks described above.